Bivalent SIRT1 inhibitors

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• 作者：Juan Wang¹ ; Wenwen Zang¹ ; Jiajia Liu¹ ; Weiping Zheng ; ^{wzheng@ujs.edu.cn}
• 关键词：β-NAD+ ; β-nicotinamide adenine dinucleotide ; NAM ; nicotinamide ; 2&prime ; -O-AADPR ; 2&prime ; -O-acyl-ADP-ribose ; RP-HPLC ; reversed-phase high performance liquid chromatography ; HRMS ; high-resolution mass spectrometry ; EDC-MeI ; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide ; DIC ; N ; N&prime ; -diisopropylcarbodiimide ; HBTU ; 2-(1H-benzotriazole-1-yl)-1 ; 1 ; 3 ; 3-tetramethylaminium hexafluorophosphate ; HOBt ; N-hydroxybenzotriazole ; NMM ; N-methylmorpholine ; EDC-HCl ; 1-(3-dimethylaminopropyl)-3-ethyl
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：27
• 期：2
• 页码：180-186
• 全文大小：900 K
• 卷排序：27

文摘

In the current study, bivalent compounds 1–17 constructed by covalently linking the ɛ-amino group of lysine in a tripeptidic scaffold to a functionality via a linker were prepared and examined for their inhibitory potencies against SIRT1, a prototypical member of the β-nicotinamide adenine dinucleotide (β-NAD+)-dependent sirtuin family of protein Nε-acyl-lysine deacylases. A few of them were found to be stronger SIRT1 inhibitors than the Nɛ-acetyl-lysine-containing monovalent counterparts 18 and 19. As exemplified with compounds 6 and 18, a bivalent SIRT1 inhibitor could exhibit a greater degree of inhibitory selectivity among SIRT1/2/3 than the corresponding monovalent counterpart. This study has laid a foundation for the future development of superior bivalent inhibitors against the (patho)physiologically and therapeutically important sirtuin family of deacylase enzymes.